U.S. patent number 3,957,982 [Application Number 05/535,575] was granted by the patent office on 1976-05-18 for method for contraception by the application of combination-type sequential preparations.
This patent grant is currently assigned to Schering Aktiengesellschaft. Invention is credited to Ursula Lachnit-Fixson, Alan G. Pitchford.
United States Patent |
3,957,982 |
Lachnit-Fixson , et
al. |
May 18, 1976 |
**Please see images for:
( Certificate of Correction ) ** |
Method for contraception by the application of combination-type
sequential preparations
Abstract
Method of contraception in which an estrogen and a progestagen
are orally administered daily for 21 days, the first 4-6 days at a
low contraceptively effective daily dose, the next 4-6 days at a
daily estrogen dose 1-2 times and a daily progestrogen dose 1-1.5
times that of the first 4-6 days, and for the next 9-11 days at a
daily estrogen dose from that of the first 4-6 days to that of the
next 4-6 days and a daily progestogen dose higher than either prior
daily dose, up to 3 times that of the initial dose, followed by 7
days without hormone administration.
Inventors: |
Lachnit-Fixson; Ursula (Berlin,
DT), Pitchford; Alan G. (High Hurstwood, near
Uckfield, EN) |
Assignee: |
Schering Aktiengesellschaft
(Berlin & Bergkamen, DT)
|
Family
ID: |
5902211 |
Appl.
No.: |
05/535,575 |
Filed: |
December 23, 1974 |
Foreign Application Priority Data
|
|
|
|
|
Dec 21, 1973 [DT] |
|
|
2365103 |
|
Current U.S.
Class: |
514/170;
514/843 |
Current CPC
Class: |
A61K
45/06 (20130101); Y10S 514/843 (20130101) |
Current International
Class: |
A61K
45/00 (20060101); A61K 45/06 (20060101); A61K
031/56 () |
Field of
Search: |
;424/238,239 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Roberts; Elbert L.
Attorney, Agent or Firm: Millen, Raptes & White
Claims
What is claimed is:
1. A method of contraception which comprises administering for 21
successive days to a female of child-bearing age a combination of
an estrogen and a progestogen, for the first 4-6 days in a low but
contraceptively effective daily dosage corresponding in estrogenic
activity to 0.020-0.050 mg. of 17.alpha.-ethinylestradiol and in
progestogenic activity to 0.050-0.125 mg. of d-norgestrel; for the
next 4-6 days, at an estrogen daily dosage from 1-2 times the
initial daily low dosage and at a progestogen daily dosage of from
1-1.5 times the dosage of the first 4-6 days; and for the next 9-11
days, at a daily estrogen dosage of from the initial daily dosage
to the subsequent daily dosage and at a progestogen daily dosage
higher than the previous daily dosages of up to 3 times that of the
first daily dosage and corresponding in progestogenic activity to
0.100-0.250 mg. of d-norgestrel, followed by about 7 days without
progestogen and estrogen administration.
2. A method according to claim 1 wherein the estrogen and
progestogen are administered orally.
3. A method according to claim 1 wherein the estrogen and
progestogen are administered in admixture.
4. A method according to claim 1 wherein the first combination of
estrogen and progestogen is administered for 6 days, the second
combination of estrogen and progestogen is administered for 5 days,
the third combination of estrogen and progestogen is administered
for 10 days and a placebo is administered for 7 days.
5. A method according to claim 1 wherein in at least one of the
stages the estrogen is 17.alpha.-ethinylestradiol.
6. A method according to claim 5 wherein the estrogen in all three
stages is 17.alpha.-ethinylestradiol.
7. A method according to claim 1 wherein in at least one of the
stages the progestogen is d-norgestrel.
8. A method according to claim 7 wherein the progestogen in all
three stages is d-norgestrel.
9. A method according to claim 1 wherein in at least one of the
stages the progestogen is cyproterone acetate or
17.alpha.-ethinyl-19-nortestosterone acetate.
10. A method according to claim 1 wherein in all three stages the
progestogen is d-norgestrel and the estrogen is
17.alpha.-ethinyl-19-nortestosterone acetate and they are
administered orally in admixture.
11. A method according to claim 9 wherein 0.040 - 0.090 mg., 0.050
- 0.125 mg. and 0.100 - 0.250 mg., respectively, of d-norgestrel
and 0.020 - 0.050 mg., 0.030 - 0.050 mg. and 0.025 - 0.050 mg.,
respectively, of 17.alpha.-ethinylestradiol are administered in the
first, second and third stages.
12. The three-stage oral contraceptive composition comprising 21
separate dosage units, adapted for successive daily oral ingestion,
consisting essentially of:
as the first stage, 4-6 dosage units containing, in admixture with
a pharmaceutically acceptable carrier, a combination of an estrogen
and a progestogen at low but contraceptively effective respective
dosages corresponding in activity to 0.020-0.050 mg. of
17.alpha.-ethinyl-estradiol and in progestogenic activity to
0.050-0.125 mg. of d-norgestrel followed by, as the second stage,
4-6 dosage units containing, in admixture with a pharmaceutically
acceptable carrier, a combination of an estrogen at a dosage from
the same to twice the dosage of the first stage, and a progestogen
at a dosage from 1-1.5 times the dosage of the first stage,
followed by, as the third stage, 9-11 dosage units containing, in
admixture with pharmaceutically acceptable carrier, a combination
of an estrogen at a dosage from that of the first stage to that of
the second stage, and a progestogen at a higher dosage than the
first and second stages up to three times that of the first stage
and corresponding in progestogenic activity to 0.100-0.250 mg. of
d-norgestrel, optionally followed by, as the fourth stage, 7 dosage
units free of estrogen and progestogen.
13. A composition according to claim 12 wherein the dosage units
are in the form of tablets.
14. A composition according to claim 12 wherein in at least one of
the stages the estrogen is 17.alpha.-ethinylestradiol.
15. A composition according to claim 14 wherein the estrogen in all
three stages is 17.alpha.-ethinylestradiol.
16. A composition according to claim 12 wherein in at least one of
the stages the progestogen is d-norgestrel.
17. A composition according to claim 16 wherein the progestogen in
all three stages is d-norgestrel.
18. A composition according to claim 12 wherein in at least one of
the stages the progestogen is cyproterone acetate or
17.alpha.-ethinyl-19-nortestosterone acetate.
19. A composition according to claim 12 wherein in all three stages
the progestogen is d-norgestrel and the estrogen is
17.alpha.-ethinyl-19-nortestosterone acetate.
20. A composition according to claim 19 wherein 0.040 - 0.090 mg.,
0.050 - 0.125 mg. and 0.100 - 0.250 mg., respectively, of
d-norgestrel and 0.020 - 0.050 mg., 0.030 - 0.050 mg. and 0.025 -
0.050 mg., respectively, of 17.alpha.-ethinylestradiol and in the
first, second and third stages.
Description
BACKGROUND OF THE INVENTION
Numerous hormonal methods for contraception are known, i.e., the
oral administration of combination-type preparations, e.g.,
"Ovulen", "Anovlar", "Lyndiol" and similar combinations of
estrogenic and gestagenic active agents. Also conventional is the
administration of purely sequential preparations, such as, for
example, "Ovanone", etc., wherein first an estrogen is administered
at a high dosage in the absence of gestagen, over a period of 7
days, and thereafter the estrogen is administered at the same high
dosage in combination with a relatively high amount of gestagen
over a period of 15 days, with the next 6 days being a blank period
without administration of estrogenic or gestagenic agent in order
to mimic the normal 28-day menstrual cycle of the woman.
The administration of modified sequential preparations is likewise
conventional, such as, for example, "Kombiquens", "Tri-Ervonum" and
"Oraconal", etc., wherein first an estrogen is administered at a
high dosage in combination with a low amount of gestagen over a
period of 16 days, and subsequently the estrogen is administered
over a period of about 7 days at the same high dosage in
combination with an amount of gestagen about 5-10 times the
original amount. See U.S. Pat. No. 3,568,828. To adapt to the
natural 28-day cycle of the female, a five-day hormone-free period
follows the administration of these preparations wherein placebos
or any desired other non-contraceptive effective agents are taken,
such as, for example, tonics, iron supplements, etc.
It is also known to administer two-stage combination-type oral
contraceptives, with a combination of an estrogen at a low dosage
and a progestogen at a low dosage first being administered for
10-12 days and subsequently a combination of the same dosage of
estrogen and a dosage of progestogen increased to 2-3 times as
much, is ingested for 11-9 days. To adapt to the normal about
28-day female cycle, a 5-7 day hormone-free period follows in which
no estrogens or progestogens are ingested. For continuity of
dosage, a placebo or a nonhormonal effective agent is usually
administered during this period. See application Ser. No. 350,590,
filed Apr. 12, 1973.
Disadvantages inherent in the administration of the aforementioned
pure and modified sequential products involving the administration
of relatively high doses of estrogen, are, in addition to the usual
symptoms due to excessive estrogen, e.g., gastrointestinal
disturbances, nausea, weight gain with formation of edema, etc., an
increase in the risk of thromboembolic disease. These disadvantages
would be avoided by the administration of the above-described
two-stage combination contraceptives, but in the latter it is
desirable to improve the compatibility and/or the control of the
cycle.
In application Ser. No. 486,757, filed July 9, 1974, there is
claimed a contraceptive method in which a low but contraceptively
effective daily dosage of an estrogen and a progestogen are
administered for 10-12 days and thereafter a combination of an
estrogen and a progestogen are administered at slightly higher
dosages.
SUMMARY OF THE INVENTION
According to this invention, reliable contraception is achieved by
administering for 21 successive days to a female of child-bearing
age a combination of an estrogen and a progestogen, for the first
4-6 days in a low but contraceptively effective daily dosage; for
the next 4-6 days, at an estrogen daily dosage from 1-2 times the
initial daily low dosage and at a progestogen daily dosage of from
1 - 1.5 times the dosage of the first 4-6 days; and for the next
9-11 days, at a daily estrogen dosage of from the initial daily
dosage to the subsequent daily dosage and at a progestogen daily
dosage higher than the previous daily dosages of up to 3 times that
of the first daily dosage, followed by 7 days without progestogen
and estrogen administration.
The total number of days during which the progestogen and estrogen
combinations are administered daily is 21. These are followed by 7
days free of hormone administration to approximate the natural
28-day menstrual cycle.
In a composition aspect, this invention relates to a three-stage or
a contraceptive composition comprising 21 separate dosage units,
adapted for successive daily oral ingestion, consisting essentially
of:
as the first stage, 4-6 dosage units containing, in admixture with
a pharmaceutically acceptable carrier, a combination of an estrogen
and a progestogen at low but contraceptively effective respective
dosages, followed by,
as the second stage, 4-6 dosage units containing, in admixture with
a pharmaceutically acceptable carrier, a combination of an estrogen
at a dosage from the same to twice the dosage of the first stage,
and a progestogen at a dosage from 1 - 1.5 times the dosage of the
first stage, followed by,
as the third stage, 9-11 dosage units containing, in admixture with
a pharmaceutically acceptable carrier, a combination of an estrogen
at a dosage from that of the first stage to that of the second
stage, and a progestogen at a higher dosage than the first and
second stages up to three times that of the first stage, optionally
followed by,
as the fourth stage, 7 dosage units free of estrogen and
progestogen.
DETAILED DISCUSSION
The "low but contraceptively effective dosage" employed in the
first stage means a dosage significantly lower, e.g., 60 to 20%,
preferably 50 to 30%, of the contraceptive dose conventionally
employed with a combination of the selected estrogen and
progestogen when administered conventionally in a non-sequential
manner. As will be apparent, the weight amount of the dosage at
each dosage level will depend upon the estrogenic and progestogenic
activity, respectively, of the selected components of the dosage
units.
Suitable as the estrogen component for the contraceptive method of
this invention are the conventional estrogens. The selected
estrogen should be administered in a daily dosage in the first 4-6
days equal in contraceptive activity to that of 0.020 - 0.050 mg.
daily of 17.alpha. -ethinylestradiol. The amount of estrogen
administered daily in the 4-6 days of the second phase should be
equal in contraceptive activity to a daily dosage of about 0.030 -
0.050 mg. of 17.alpha.-ethinylestradiol, i.e., 1 - 1.5 times the
first dosage level. The amount of estrogen administered daily
during the 9-11 days of the third phase should be equal in
contraceptive activity to a daily dosage of about 0.025 - 0.050 mg.
of 17.alpha.-ethinylestradiol.
In addition to 17.alpha.-ethinylestradiol, esters and ethers of
17.alpha.-ethinylestradiol are also suitable as the estrogen
component. Also suitable are, e.g., the natural estrogens, e.g.,
estrone, estradiol and estriol, and their esters, e.g., estradiol
valerate, as well as the synthetic estrogens.
17.alpha.-Ethinylestradiol is preferred.
As the progestogen component of this invention, all
progestationally active compounds are suitable. The progestogen
preferably is administered in a daily dosage in the first 4-6 days
corresponding in progestogenic activity to 0.040 - 0.090 mg. of
d-norgestrel per day. The amount of progestogen administered daily
in the 4-6 days of the second phase should be equivalent in
progestogenic activity to the daily administration of 0.050 - 0.125
mg. of d-norgestrel. The amount of progestogen administered daily
during the 9-11 days of the third phase should be equal in
progestogenic activity to the daily administration of about 0.100 -
0.250 mg. of d-norgestrel.
Suitable as the progestogen component are, e.g., progesterone and
its derivatives, e.g., 17-hydroxyprogesterone esters and 19
-nor-17-hydroxyprogesterone esters, 17.alpha.-ethinyltestosterone,
as well as 17.alpha.-ethinyl-19-nortestosterone and the derivatives
thereof. The term "derivatives" as used herein means compounds
which are formed by the introduction of an additional double bond
or double bonds, by substitution or by the production of a
functional derivative, e.g., esters, ethers, ketals, etc.
Such additional double bonds can be present, inter alia, in the
1(2)-, 6(7)- and/or 16(17)-position. Suitable substituents are,
among others, halogen, particularly fluorine, chlorine and bromine
atoms, lower alkyl, especially the methyl group, alkenyl, alkinyl,
especially the ethinyl group, and/or the hydroxy group, each of
which can be in the 4-, 6-, 7-, 16- and/or 17-position, as well as
methylene groups which can be in the 1(2)-, 6(7)- 15(16)- and/or
16(17)-position. Suitable esters are the esters of acids
customarily employed in the steroid chemistry for the
esterification of the steroid hydroxy groups, e.g., hydrocarbon
carboxylic acids, especially alkanecarboxylic acids, of 1-11 carbon
atoms, more preferably 2-5 carbon atoms. Examples of ethers are
alkyl, e.g., of 1-11 carbon atoms, benzyl and tetrahydropyranyl
ethers. Examples of ketals are those of .alpha.,.beta.-,
.alpha.,.gamma. - and .beta., .gamma. -alkanediols, e.g., of 1-8
carbon atoms, especially ethanediol and the propanediols.
Preferred progestogens are d-norgestrel,
17.alpha.-ethinyl-19-nortestosterone acetate, and cyproterone
acetate.
The combination of progestogen and estrogen can be the same or also
different in the first and second or third stages. If a different
progestogen and/or estrogen is utilized in the first, second and/or
third stages, the present invention has the additional advantage
above and beyond the aforedescribed advantages in that the side
effects of a specific progestogen (or estrogen) are reduced or
eliminated, in that such progestogen (or estrogen) is administered
in one or two stages only while in the other stage or stages,
another progestogen (or estrogen) having a competitive array of
side effects is administered.
Thus, it is possible, for example, to utilize in one stage the
estrogen in combination with a progestogen derived from
testosterone or 19-nortestosterone and having in the
17.alpha.-position, optionally a substituted hydrocarbon group.
These (19-nor-) testosterone derivatives generally exhibit a low
androgenic side effect. In one of the other stages, the estrogen
can then be used in combination with a progestogen derived from
progesterone which lacks the androgenic side effect inherent in the
testosterone or 19-nortestosterone compounds. Particularly
advantageous progestogens are those possessing an antiandrogenic
side effect in addition to the progestational activity.
It is also possible, for example, to employ, in one stage, a
progestogen in combination with an estrogen derived from
17.alpha.-ethinylestradiol. These estrogens generally have a lessor
gastric compatibility and exert a stronger effect on carbohydrate
and fat metabolism. In one of the other stages, the progestogen can
then be utilized in combination with an estrogen derived from a
natural estrogen lacking the above-described side-effects.
If, in the first, second and/or third stages, different
progestogens are utilized, it is preferred to employ in the first
and second stages, a progestogen which is a testosterone or
19-nortestosterone derivative and, in the third stage, a
progestogen which is a progesterone derivative.
If, in the first and second or third stages, different estrogens
are used, the preferred embodiment is to employ, in the first and
second stages, an estrogen which is a 17.alpha.-ethinylestradiol
derivative and, in the third stage, an estrogen which lacks a
17.alpha.-ethinyl group.
The estrogenic and progestational effective agent components are
preferably administered together orally, but they can also be
administered separately or parenterally. For this purpose, the
effective agents are processed, together with the usual additives,
vehicles and/or flavor-ameliorating agents employed in galenic
pharmacy, in accordance with known methods. For the preferred oral
administration, especially suitable are tablets, dragees, capsules,
pills, suspensions or solutions, and for parenteral application
especially oily solutions, such as, for example, sesame oil or
castor oil solutions which can optionally additionally contain a
diluent, e.g., benzyl benzoate or benzyl alcohol.
For the preferred oral application, the three-stage
combination-type contraceptives are preferably packaged in the form
of a pharmaceutical kit in which the daily dosages are arranged for
proper sequential ingestion.
Accordingly, this invention also relates to pharmaceutical packs
which contain combination-type contraceptives in 28 dosage units in
a synchronized, fixed sequence, wherein the sequence or arrangement
of the dosage units corresponds to the stages of daily
administration.
The pharmaceutical pack can be, e.g., in the form of a see-through
package with 28 dosage units arranged sequentially and consisting
of 6 dragees for the first stage, followed by 5 dragees for the
second stage, followed by 10 dragees for the third stage, and
followed by 7 placebos, one dragee to be taken daily over a period
of 28 days.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following preferred specific
embodiments are, therefore, to be construed as merely illustrative
and not limitative of the remainder of the disclosure in any way
whatsoever.
______________________________________ EXAMPLE 1 Composition of a
Dragee in Each of the Stages ______________________________________
1st Stage (6 Dragees): 0.030 mg. 17.alpha.-Ethinylestradiol 0.050
mg. d-Norgestrel 33.170 mg. Lactose 18.000 mg. Corn starch 2.100
mg. Polyvinylpyrrolidone 1.650 mg. Talc 55.000 mg. Total weight
which is supplemented to about 90 mg. with a customary sugar
mixture. 2nd Stage (5 Dragees): 0.050 mg.
17.alpha.-Ethinylestradiol 0.050 mg. d-Norgestrel 33.150 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650
mg. Talc 55.000 mg. Total weight which is supplemented to about 90
mg. with a customary sugar mixture. 3rd Stage (10 Dragees): 0.040
mg. 17 .alpha.-Ethinylestradiol 0.125 mg. d-Norgestrel 33.085 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650
mg. Talc 55.000 mg. Total weight which is supplemented to about 90
mg. with the usual sugar mixture. EXAMPLE 2 Composition of a Dragee
for Each Stage ______________________________________ 1st Stage (6
Dragees): 0.030 mg. 17.alpha.-Ethinylestradiol 0.050 mg.
d-Norgestrel 33.070 mg. Lactose 18.000 mg. Corn starch 2.100 mg.
Polyvinylpyrrolidone 1.650 mg. Talc 0.100 mg. Magnesium stearate
55.000 mg. Total weight which is supplemented to about 90 mg. with
the usual sugar mixture. - 2nd Stage (5 Dragees): 0.040 mg.
17.alpha.-Ethyinylestradiol 0.075 mg. d-Norgestrel 33.035 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650
mg. Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight which
is supplemented to - about 90 mg. with the usual sugar mixture. 3rd
Stage (10 Dragees): 0.030 mg. 17.alpha.-Ethinylestradiol 0.125 mg.
d-Norgestrel 32.995 mg. Lactose 18.000 mg. Corn starch 2.100 mg.
Polyvinylpyrrolidone 1.650 mg. Talc 0.100 mg. Magnesium stearate
55.000 mg. Total weight which is supplemented to about 90 mg. with
the usual sugar mixture. EXAMPLE 3 Composition of a Dragee for Each
Stage ______________________________________ 1st Stage (6 Dragees):
0.030 mg. 17.alpha.-Ethinylestradiol 0.050 mg. d-Norgestrel 33.070
mg. Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone
1.650 mg. Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight
which is supplemented to about 90 mg. with the usual sugar mixture.
2nd Stage (5 Dragees): 0.050 mg. 17.alpha.-Ethinylestradiol 0.075
mg. d-Norgestrel 33.025 mg. Lactose 18.000 mg. Corn starch 2.100
mg. Polyvinylpyrrolidone 1.650 mg. Talc 0.100 mg. Magnesium
stearate 55.000 mg. Total weight which is supplemented to about 90
mg. with the usual sugar mixture. 3rd Stage (10 Dragees): 0.040 mg.
17.alpha.-Ethinylestradiol 0.125 mg. d-Norgestrel 32.985 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650
mg. Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight which
is supplemented to about 90 mg. with the usual sugar mixture.
EXAMPLE 4 Composition of a Dragee for Each Stage
______________________________________ 1st Stage (6 Dragees): 0.050
mg. 17.alpha.-Ethinylestradiol 0.050 mg. d-Norgestrel 33.050 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650
mg. Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight which
is supplemented to about 90 mg. with the usual sugar mixture. 2nd
Stage (5 Dragees): 0.050 mg. 17.alpha.-Ethinylestradiol 0.75 mg.
d-Norgestrel 33.025 mg. Lactose 18.000 mg. Corn starch 2.100 mg.
Polyvinylpyrrolidone 1.650 mg. Talc 0.100 mg. Magnesium stearate
55.000 mg. Total weight which is supplemented to about 90 mg. with
the usual sugar mixture. 3rd Stage (10 Dragees): 0.050 mg.
17.alpha.-Ethinylestradiol 0.125 mg. d-Norgestrel 32.975 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.640
mg. Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight which
is supplemented to about 90 mg. with the usual sugar mixture.
EXAMPLE 5 Composition of a Dragee per Stage
______________________________________ 1st Stage (6 Dragees): 3.000
mg. Estradiol valerate 0.050 mg. d-Norgestrel 30.200 mg. Lactose
18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg.
Talc 55.000 mg. Total weight which is supplemented to about 90 mg.
with the usual sugar mixture. 2nd Stage (5 Dragees): 5.000 mg.
Estradiol valerate 0.050 mg. d-Norgestrel 28.200 mg. Lactose 18.000
mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg. Talc
55.000 mg. Total weight which is supplemented to about 90 mg. with
the usual sugar mixture. 3rd Stage (10 Dragees): 4.000 mg.
Estradiol valerate 0.125 mg. d-Norgestrel 29.125 mg. Lactose 18.000
mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg. Talc
55.000 mg. Total weight which is supplemented to about 90 mg. with
the usual sugar mixture. ______________________________________
The preceding examples can be repeated with similar success by
substituting the generically and specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and
without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *